The principal objective of these studies is to determine host and viral factors which influence the genetically-controlled resistance of inbred mouse strains to street rabies virus (SRV). It has been shown that the two segregating genes of SJL and CBA/J mice responsible for resistance to SRV were allelic (identical). In contrast, resistance genes of SJL and BALB/c, SJL and DBA/2, CBA/J and BALB/c and CBA/J and DBA/2 were nonallelic (not identical). In these instances there was one different resistance gene for each strain. Cell transfer studies have shown that nonimmune spleen cells of resistant mouse strains did not protect unirradiated H-2 histocompatible susceptible strains against SRV. In contrast, ten million immune spleen cells of resistant BALB/c (nu/+) mice were highly effective in protecting susceptible BALB/c (nu/nu) mice if cells were inoculated 1-7 days before SRV. Furthermore, susceptible athymic mice which had been infected 3 days previously with SRV, and were known to have spinal cord infections, also were protected by immune cells. Anti-SRV antibody alone did not protect these mice. Additional experiments showed that immune spleen cells harvested from BALB/c (nu/+) mice 3-370 days after SRV infection transferred resistance against SRV. All nu/nu survivors which received immune cells had moderate (1:320) to high (1:5120) serum neutralizing antibody titers. It also was determined that cyclophosphamide abolished the resistance of SJL mice to SRV. Prior to their death, none of these mice was able to produce neutralizing antibody to SRV. In contrast, SJL mice inoculated with SRV after the immunosuppressive effects of cyclophosphamide had abated produced neutralizing antibody and survived. Additional experiments showed that passively transferred immune cells or immune serum protected SJL mice which were unable to produce neutralizing antibody against SRV following cyclophosphamide treatment. Direct infection of the CNS of SJL mice via intranasal or intracerebral challenge determined that serum anti-SRV neutralizing antibody was essential to genetic resistance as well as CNS immunity. Similar antibody within the CSF was not associated with resistance to SRV.